1,3-dimethyl-4,5-di(p-substituted phenyl)6h-pyrrolo(2,3-c)pyrazoles in treating inflammation

ABSTRACT

Novel 1,3-dimethyl-4,5-di(p-substituted phenyl)-6H-pyrrolo(2,3c)pyrazoles and novel intermediates useful in their synthesis. The compounds are useful as anti inflammatory and anti-pyretic agents.

United States Patent [191 Paris et al.

[ 1,3-DIMETHYL-4,5-Dl(P-SUBSTITUTED PHENYL)6H-PYRROLO(2,3-C) PYRAZOLES IN TREATING INFLAMMATION [75] Inventors: Gerard Yvon Paris, Duvernay,

Quebec, Canada; Leo Ralph Swett,

21 App]. No.: 341,443

Related US. Application Data [60] Continuation-impart of Ser. No. 257,732, May 30, 1972, abandoned, which is a division of Ser. No. l12,767, Feb. 4, l97l, Pat. N0. 3,70l,785.

[52] US. Cl. 424/272 [51] Int. Cl ..A61k 27/00 [58] Field of Search 424/272 June 28, 1974 [56] References Cited FOREIGN PATENTS OR APPLICATIONS 168,299 2/1965 U.S.S.R 260/310 R OTHER PUBLICATIONS Chem. Abst., Vol. 62, 2339 f(1965). Chem. Abst., Vol. 6216256 (1965).

Primmy Examiner-Stanley J. Friedman Attorney, Agent, or Firm-Robert L. Niblack; Joyce R. Krei; Vincent A. Mallare ABSTRACT Novel l,3-dimethyl-4,5-di(p-substituted phenyl)-6H- pyrr0lo[2,3-c]pyrazoles and novel intermediates useful in their synthesis. The compounds are useful as anti inflammatory and anti-pyretic agents.

13 Claims, No Drawings CROSS-REFERENCE TO RELATED APPLlCATlONS This application is a continuation-in-part of copending application, Ser. No. 257,732, filed May 30,

tion of US. Ser. No. 112,767, filed Feb. 4, 1971, now

1972, now abandoned, which was a divisional applica- R US. Pat. No. 3,701,785, issued Oct. 31, 1972.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel 1,3-dimethyl-4,5-di(psubstituted phenyl)-6H-pyrrolo[2,3-c]pyrazoles representedby the formula CH3 R2 wherein R is hydrogen or methyl; R is hydrogen, C -C alkyl, C C alkoxy or halo; and R is benzoyl, halosubstituted benzoyl, di(C -C )alkylamino(C C )alkyl, 2-thiophenecarbonyl, hydrogen or C -C alkyl.

The term C -C alkyl refers to straight and branched chain alkyls and includes methyl, ethyl, npropyl, iso-propyl, n-butyl, sec-butyl and tert-butyl.

The term C CJ, alkoxy" includes methoxy, ethoxy; propoxy and butoxy.

The term halo as used herein includes chloro, fluoro, bromo and iodo. The compounds of this invention are useful as antiinflammatory and anti-pyretic agents when administered to mammalian patients in dosages of from 10 to, 50 mg./kg. of body weight daily, preferably in divided dosages (i.e., 175 to 875 mg. four times daily). The anti-inflammatory-activity of the compounds was established in the carrageenin rat paw edema test (Winter et aL, Proc. Soc. Exp. Biol. Med. 11 l, 554 [1962]).

The anti-pyretic activity was established by the yeast-' induced fever test in rats.

The preferred method of preparing the compounds of this invention is represented by the following reac-; tion scheme: 1

1 gen atmosphere for 48 hours using a Barrett trap to col- Compoundsof the formula II EXAMPLE 1 5- [a-( p-Methoxybenzoyl )-p-Methoxybenzylamino 1,3-Dimethyl-Pyrazole Hydrochloride A solution of p-anisoin (27.2 g., 0.10 mole), 1,3- dimethyl-S-aminopyrazole (12.2 g., 0.11 mole) and p-toluene-sulfonic acid monohydrate (0.95 g., 0.005 mole) in benzene ml.) was refluxed under nitrolect the water'formed (1 ml.). The reaction mixture was filtered and the filtrate was evaporated to dryness to yield an oil (37.8 g. A part of this oil was dissolved in alcohol and treated with ethanolic picric acid. The picrate melted at 168-169.

' Analysis Calcd. for C H N O C, 54.54; H, 4.41; N, 14.14;

0. 26.92 Found: C, 54.58; H. 4.50; N, 14.20;

Analysis Calcd.'for C H- ClN O C. 62.76;

Found: C. 62.61

EXAMPLE 2 Analysis Calcd. for C H,,C1,N -,O: C. 60.97: H.

4.58; N. Found: C. 60.8];11. 4.0

EXAMPLE 3 5-[oz-( p-Methylbenzoyl)-p-Methylbenzylamino]-l ,3- Dimethylpyrazole Hydrochloride A solution of 4,4'-dimethylbenzoin (14.4 g., 0.060 mole), 1,3-dimethyl-5-aminopyrazole (7.3 g., 0.066 mole) and p-toluenesulfonic acid monohydrate (0.57 g., 0.003 mole) was refluxed in benzene (80 ml.) for 24 hours. The picrate was obtained as described in Example 1, mp. l95l97.

Analysis Calcd. for C H H O C. 57.65;

H. 4. Found: C. 57.68; H. 4.

1,3-Dimethy1-4,5-di(p-Methoxyphenyl )-6H-Pyrrolo- [2,3-c Pyrazole A stirred mixture of crude 5-[a-(p-methoxybenzoyl)- p-methoxybenzylamino]-1,3-dimethylpyrazole (7.3 g., 0.02 mole), aniline (5.59 g., 0.06 mole) and aniline hydrobromide (1.7 g., 0.01 mole) was heated at 170 for 3 hours. The reaction mixture was evaporated to dryness under vacuum to remove the excess aniline. The viscous residue was dissolved in 100 ml. of methanol and treated with 50 ml. of amberlite IRA-400 resin in the OH form (previously washed with methanol). The resin was removed by filtration. The filtrate was evaporated to dryness to yield an oil which was treated with 200 ml. of ether. The insoluble pyrrolo[2,3-c]pyrazole was filtered. Yield 2.5 g. (35%) mp. 230232.

Analysis Culcd. for C H,,N;,O C. 72.60; H. 6.09; N, 12.10;

0, 9.21 Found: C. 72.42; H. 6.14; N. 12.04;

EXAMPLE 5 1 ,3-Dimethyl-4,5-di-(p-chlorophenyl )-6H- pyrrolo[2.3-c]pyrazole A stirred mixture of crude 5-[oz-(p-chlorobenzoyl)-pchlorobenzylamino]-1,3-dimethylpyrazole (24.8 g., 0.066 mole), aniline (18.4 g., 0.198 mole) and aniline hydrobromide (5.7 g., 0.033 mole) was heated at 170 for 1V2 hours. The reaction mixture was evaporated to dryness to yield an oil. Treatment with amberlite [RA- 400 in the OH form, filtration and evaporation to dryness gave a residue which was treated with petroleumether (b.p. 120) (some tar remained insoluble). The petroleum-ether extracts were cooled and the solid formed was filtered. Yield 8.4 g. m.p. 190195 C. The crude solid was treated with water, filtered and crystallized from alcohol, m.p. 226228.

Analysis Calcd. for C H Cl N z C, 64.06; H, 4.24; N, 11.79 Found: C. 64.10; H, 4.33; N, 11. 4

EXAMPLE 6 1.3-Dimcthyl-4.5-di(p-tolyl )-6H-pynolol 2.3= clpyrazole A stirred mixture of crude 5-[a-(p-methylbenzoyl)- p-methyl-benzylamino]-l ,3-dimethylpyrazole 19.4 g., 0.058 mole), aniline (16.2 g., 0.174 mole) and aniline hydrobromide (5.1 g., 0.029 mole) was heated at 170 for 3 hours. The product was isolated as described in Example 4. Yield 5.5 g., m.p. 238240 (from alcohol).

Analysis Calcd. for C H N C, 79.97; H. 6.71; O. 13.32 Found: C, 79.71; H. 6.77; O, 13.55

EXAMPLE 7 l,3-Dimethyl-4,5-diphenyl-6H-pyrrolo[ 2.3- c]pyrazo1e A solutionof benzoin (21.23 g., 0.10 mole), 1,3- dimethyl-S-aminopyrazole (12.2 g., 0.10 mole) and p-toluene-sulfonic acid monohydrate (0.95 g., 0.005 mole) in ml. of benzene was refluxed for 14 hours under nitrogen atmosphere (1.6 ml. of water was collected). The reaction mixture was evaporated to dryness to yield an oil.

A part of the crude oil 12.22 g., 0.04 mole) was heated with aniline (1 1.8 g., 0.12 mole) and aniline hydrobromide (3.42 g., 0.02 mole) at for 3 hours. The product was isolated as described in Example 4, except that the residual oil was dissolved in a minimum of alcohol and let stand. Yield 4.0 g., (35%), mp. 130, solidified and melted at 21021 1.

Analysis Calcd. for C H N C, 79.41; H. 5.97; N. 14.62 Found: C. 79.35; H. 5.96; N 1444 EXAMPLE 8 1,3,6-Trimethyl-4,5-diphenylpyrrolo[ 2,3-c]pyrazo1e To a stirred solution of 1,3-dimethyl-4,5-diphenyl- 6H-pyrrolo[2,3-c]pyrazole (1.44 g., 0.005 mole) in 24 m1. of N,N-dimethylformamide was added sodium hydride (0.23 g., 0.005 mole). The reaction mixture was stirred for 1 hour at 25. Methyl iodide (0.71 g., 0.005 mole) dissolved in 10 ml. of N,N-dimethylformamide was added dropwise. After the addition was over. the stirring was continued for 17 hours at room temperature. Evaporation of the solvent yielded a solid which was crystallized from alcohol, 0.6 g. (40%), mp. 176-177.

Analysis Calcd. for C H M: C, 79.70; H. 6.35; N, 13.94 Found: C, 79.62;H, 6.58; N 13.74

EXAMPLE 9 Analysis Calcd. for Cg ZbClNgOi C. 73.32; H. 4.73; N, 9. Found: C 73.21; H, 4.67; N, 9.

EXAMPLE 1,3 ,6-Trimethyl-4,5-di( p-methoxyphenyl )-pyrro1o- [2,3-c]pyrazole The reaction of 1,3-dimethyl-4,5-di(pmethoxyphenyl)-6H-pyrrolo[2,3-c]pyrazole (3.5 g., 0.01 mole), sodium hydride (0.46 g., 0.01 mole) and methyl iodide (1.4 g., 0.01 mole) in N,N-dimethylformamide, as described in Example 8, gave 2.7 g., (75%) of product, mp. l791 81. The analytical sample melted at 180-182 (from alcohol).

Analysis Calcd. for C H N O z C, 73.11; H. 6.41; N. 11.63 Found: C, 72.89; H 6.51; N. 11.73

EXAMPLE 1 l 1 .3-Dimethyl-4,5-di( p-methoxyphenyl )6-ben2oy1- pyrr0lo-[2,3-c]pyrazo1e The reaction of 1 ,3-dimethyl-4,5-di(pmethoxyphenyl)-6H-pyrrolo[2,3-c]pyrazole (1.74 g., 0.005 mole), sodium hydride (0.23 g., 0.005 mole) and benzoyl chloride (0.71 g., 0.005 mole) in m1. of N,N-dimethylformamide, as described in Example 8, yielded 1.5 g., (66%) mp. 146-150. The analytical sample melted at 162-163.

Analysis Calcd. for C ,;H N 0 C, 74.48; H. 5.58; N, 9.31;

Found: CI 74128; H, 5.69; N. 9.24;

EXAMPLE l2 1,3-Dimethyl-4,5-di(p-methoxyphenyl)-6-(pch1orobenzoyl)pyrr0lo[2,3-c]pyrazole The reaction of 1 ,3-dimethyl-4,5-di-( pmethoxyphenyl)-6Hpyrro1o[2,3-c]pyrazole (3 .47 g. 0.01 mole), sodium hydride (0.46 g., 0.01 mole) and p-chlorobenzoyl chloride 1.75 g., 0.01 mole) in 30 ml. of N,N-dimethylformamide, as described in Example 8, gave 2.7 g. (56%) of product, m.p. l76178. The analytical sample melted at 178179.

Analysis Calcd. for C ,,H .,ClN,-,O;,: C, 69.20; 111, 4.98; CI, 7.30;

N, 8.65; O, 9.88 Found: C, 69.34; H, 4.98; CI, 7 52 EXAMPLE l3 l,3,6-Trimethyl-4,5-di-(p-tolyl)pyrro1o[ 2,3-c pyrazole The reaction of 1,3-dimethyl-4,5-di-(p-tolyl)-6H- pyrrolo[2,3-c]pyrazole (1.6 g., 0.005 mole), sodium hydride (0.23 g., 0.005 mole) and methyl iodide (0.71 g., 0.005 mole) in 25 ml. of N,N-dlimethylformamide as described in Example 8 yielded 0.7 g. (44%) of product, m.p. l82184.

Analysis Calcd. for C H N z C, 80.21; H, 7.04; N, 12.75 Found: C. 80.40; H, 7.18; N, 12.78

EXAMPLE 14 l,3-Dimethyl-4,5-di-( p-tolyl)-6-1benzoylpyrrolo [2,3- c]pyrazole The reaction of l,3-dimethyl-4,5-di-(p tolyl)-6H- pyrrolo[2,3-c]pyrazole (1.6 g., 0.005 mole), sodium hydride (0.23 g., 0.005 mole) and benzoyl chloride (0.71 g., 0.005 mole) in 25 ml. of N,N-dimethylformamide as described in Example 8 yielded 0.4 g. (19%) of product, m.p. l98200.

Analysis Calcd. for C H N O: C, 80.16; H .0 l

. 6 N. 10.02 Found: C. 80.26; H, 6.

EXAMPLE l5 1 ,3-Dimethyl-4,5di-( p-tolyl )-6-(p-ch1orobenzoyl pyrrolo[2,3-c]pyrazole The reaction in 1,3-dimethyl-4,5-di-(p-tolyl)-6H- pyrrolo[2,3-c]pyrazo1e (1.6 g., 0.005 mole), sodium hydride (0.23 g., 0.005 mole) and p-chlorobenzoyl chloride (0.88 g., 0.005 mole) in 25 ml. of N,N-dimethylformamide gave 0.04 g., of product 17%), mp. 2- 04206.

Analysis Calcd. for C H CIN O: C. 74.08; H, 5.33; N. 9.2 Found: C. 74.20; H. 5.42; N, 9.2

EXAMPLE l6 1 ,3 ,6-Trimethyl-4,5-di-( p-chlorophenyl )-pyrrolo- [2,3-clpryazole The reaction of 1 ,3-dimethyl-4,5-di-(pchlorophenyl)-6H-pyrrolo[2,3-c]pyrazole (1.4 g., 0.0039 mole), sodium hydride (0.18 g., 0.0039 mole) and methyl iodide (0.55 g., 0.0039 mole) in 20 ml. of N,N-dimethylformamide gave the product (0.7 g.) in 49% yield, m.p. 208-210.

Analysis Calcd. for C H Cl N C 64.87; H 4.63; N, 11.

Found: C, 64.99; H 4.68; N 11 EXAMPLE 17 1 ,3-Dimethyl-4,5-di-(p-chlorophenyl )-6-benzoylpyrrolo[ 2,3-c lpyrazole The reaction of 1 ,3-dimethyl-4,5 di-( pchlorophenyl)-6H-pyrrolo[2,3-c]pyrazole (1.8 g., 0.005 mole), sodium hydride (0.23 g., 0.005 mole) and benzoyl chloride (0.71 g., 0.005 mole) in 25 ml. of N,N-dimethy1formamide yielded 0.93 g. (40%) of the desired product, m.p. 188190.

Analysis Calcd. for C ,,H,,,CI N,,O: C, 67.83; H 4.1

6; N, 3 Found: C, 68.08; H. 4.24; N l

EXAMPLE l8 1,3-Dimethyl-4,5-di-(p-chlorophenyl)-6-(pchlorobenzoyl)-pyrrolo[2,3-c]pyrazole The reaction of l,3-dimethyl-4,5-di-(pchlorophenyl)-6l-l-pyrrolo[2,3-c]pyrazole (1.8 g., 0.005 mole), sodium hydride (0.23 g., 0.005 mole) and p-chlorobenzoyl chloride (0.88 g., 0.005 mole) in 25 ml. of N,N-dimethylformamide as described in Example 8 gave the expected product in 32% yield (0.8 g.), m.p. 186188.

Analysis Culcd. for C H Cl N Oz C, 63.11; H, 3.67; N 8.49 Found: C 63.31; H 3.72; N 8.66

EXAMPLE l9 l,3-Dimethyl-4,5-di-(p-methoxyphenyl)-6-N,N- diethylaminoethyl pyrrolo[2,3-c]pyrazole To a stirred solution of 1,3-dimethyl-4,5-di-(pmethoxyphenyl)-6H-pyrrolo[2,3-clpyrazole (3.5 g., 0.01 mole) in 25 ml. of N,N-dimethylformamide was added sodium hydride (0.46 g., 0.01 mole). The reaction mixture was stirred for 2 hours at 25. Diethylaminoethyl chloride (1.4 g., 0.01 mole) dissolved in 25 ml. of N,N-dimethylformamide was added dropwise. After the addition was over, the stirring was continued for 20 hours at room temperature. Evaporation of the solvent yielded an oil. Extraction with (high boiling) petroleum-ether and evaporation of the petroleum-ether layer yielded a crude solid. Crystallization with petroleum-ether yielded 1.7 g. (37%) of product, m.p. l081 10.

Analysis Calcd. for C H MO C, 72.62; H. 7.67; N, 12.55 Found: C, 72.61; H, 7.87; N, 12.55

EXAMPLE 20 Analysis Calcd. for c.,.H. .N,0,,s: C, 68.25; H,

5. Found: C. 68.41; H, 5.

EXAMPLE 21 1-lV1ethyl-4,5-di(p-methoxyphenyl)-6H-pyrrolo [2,3- c]pyrazole A solution of p-anisoin (29.95 g., 0.11 mole), 1- methyl-S-aminopyrazole (9.71 g., 0.10 mole) and p-toluene-sulfonic acid monohydrate 1.1 g., 0.0058 mole) in benzene (150 ml.) was refluxed under nitrogen atmosphere for 5 hours using a Barrett trap to collect the water formed. The reaction mixture was filtered and the filtrate was evaporated to dryness to yield an oil (32.5 g. A part of this oil was dissolved in alcohol and treated with ethanolic picric acid. S-[a-pmethoxybenzoyl)-p-methoxybenzylamino]-1- methylpyrazole picrate melted at l186 turned red.

I Analysis Culcd. for C H- N O C. 53.79; H 4.17; N, 14.48 Found: C 54.07; H 4.26; N. 14.65

The crude oil (37 g.) was treated with aniline (36.3 g., 0.39 mole) and aniline hydrobromide (10.4 g., 0.06

mole). The stirred reaction mixture was heated to 1 10 C. for 17 hours. The reaction mixture was cooled, dissolved in 500 ml. of methanol and then treated with 200 ml. of amberlite lRA-400 resin in the OH form (previously washed with methanol). The resin was filtered and the filtrate was concentrated to a samll volume to yield 15 g. of the product as a solid, mp. 221- 223 (from methanol).

The compounds of the present invention can be incorporated into various pharmaceutically acceptable dosage forms such as tablets, capsules, pills, suspensions and the like for immediate or sustained release, by combining them with suitable carriers or diluents according to methods well known in the art. in addition to the active agent and the pharmaceutically acceptable carrier or diluent, the dosage forms may additionally include various excipients, binders, fillers, lubricating agents, flavoring and sweetening agents and the like. However, in the case of, for example, filled capsules, the compound can be the sole ingredient.

We claim:

1. A method of treating inflammation in a mammalian patient comprising orally administering to said patient a therapeutically effective amount of a compound of the formula wherein R is hydrogen or methyl; R, is hydrogen, C -C alkyl, C -C alkoxy or halo; and R is bcnzoyl. halosubstituted benzoyl, di(C,-C.,) alkylaminow t, )alkyl, 2-thiophenecarbonyl, hydrogen or C -C ulkyl.

2. The method of claim 1 wherein said compound is administered to said patient in dosages of l50 mg/kg. of body weight daily.

3. The method of claim 1 wherein R is hydrogen and R is C -C alkoxy.

4. The method of claim 1 wherein said compound is: 1 ,3-dimethyl-4,5-di-(p-methoxyphenyl )-6H- pyrrolo[2,3-c]-pyrazole.

5. The method of claim 1 wherein said compound is l ,3-dimethyl-4,5-di-(p-chlorophenyl)-6H-pyrrolo[2,3- c]pyrazole.

6. The method of claim 1 wherein said compound is: l ,3-dimethyl-4,5-di-(p-tolyl)-6H-pyrrolo[2,3- c]pyrazole.

7. The method of claim 1 wherein said compound is: l,3-dimethyl-4,5-diphenyl-6H-pyrrolo[2,3-c]pyrazole.

8. The method of claim 1 wherein said compound is: 1 ,3,6-trimethyl-4,S-diphenylpyrrolo[2,3-c]pyrazole.

9. The method of claim 1 wherein said compound is: l,3,6-trimethyl-4,5-di( p-methoxyphenyl )-pyrrolo[ 2 ,3- c]pyrazole.

10. The method of claim 1 wherein said compound is: l,3,6-trimethyl-4,5-di-(p-tolyl )-pyrrolo[2,3- c]pyrazole.

11. The method of claim 1 wherein said compound is: l,3,6-trimethyl-4,5-di-( p-chlorophenyl pyrrolo[2,3-c]pyrazole.

12. The method of claim 1 wherein said compound is: l,3-dimethyl-4,5-di(p-methoxyphenyl)-6-N,N- diethylaminoethyl-pyrrolo[ 2 ,3-c ]pyrazole.

13. The method of claim 1 wherein said compound is: 1-methyl-4,5-di(p-methoxyphenyl)-6H-pyrrolo[2,3- c]pyrazole. 

2. The method of claim 1 wherein said compound is administered to said patient in dosages of 1-50 mg./kg. of body weight daily.
 3. The method of claim 1 wherein R2 is hydrogen and R1 is C1-C4 alkoxy.
 4. The method of claiM 1 wherein said compound is: 1,3-dimethyl-4,5-di-(p-methoxyphenyl)-6H-pyrrolo(2,3-c)-pyrazole.
 5. The method of claim 1 wherein said compound is 1,3-dimethyl-4,5-di-(p-chlorophenyl)-6H-pyrrolo(2,3-c)pyrazole.
 6. The method of claim 1 wherein said compound is: 1,3-dimethyl-4,5-di-(p-tolyl)-6H-pyrrolo(2,3-c)pyrazole.
 7. The method of claim 1 wherein said compound is: 1,3-dimethyl-4,5-diphenyl-6H-pyrrolo(2,3-c)pyrazole.
 8. The method of claim 1 wherein said compound is: 1,3,6-trimethyl-4,5-diphenylpyrrolo(2,3-c)pyrazole.
 9. The method of claim 1 wherein said compound is: 1,3,6-trimethyl-4,5-di(p-methoxyphenyl)-pyrrolo(2,3-c)pyrazole.
 10. The method of claim 1 wherein said compound is: 1,3,6-trimethyl-4,5-di-(p-tolyl)-pyrrolo(2,3-c)pyrazole.
 11. The method of claim 1 wherein said compound is: 1,3,6-trimethyl-4,5-di-(p-chlorophenyl)-pyrrolo(2,3-c)pyrazole.
 12. The method of claim 1 wherein said compound is: 1,3-dimethyl-4,5-di(p-methoxyphenyl)-6-N,N-diethylaminoethyl-pyrrolo(2,3 -c)pyrazole.
 13. The method of claim 1 wherein said compound is: 1-methyl-4, 5-di(p-methoxyphenyl)-6H-pyrrolo(2,3-c)pyrazole. 